Preparation of injectable suspensions having improved injectability

ABSTRACT

Injectable compositions having improved injectability. The injectable compositions include microparticles suspended in an aqueous injection vehicle having a viscosity of at least 20 cp at 20° C. The increased viscosity of the injection vehicle that constitutes the fluid phase of the suspension significantly reduces in vivo injectability failures. The injectable compositions can be made by mixing dry microparticles with an aqueous injection vehicle to form a suspension, and then mixing the suspension with a viscosity enhancing agent to increase the viscosity of the fluid phase of the suspension to the desired level for improved injectability.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to preparation of injectable compositions.More particularly, the present invention relates to injectablesuspensions having improved injectability, and to methods for thepreparation of such injectable suspensions.

2. Related Art

Injectable suspensions are heterogeneous systems that typically consistof a solid phase dispersed in a liquid phase, the liquid phase beingaqueous or nonaqueous. To be effective and pharmaceutically acceptable,injectable suspensions should preferably be: sterile; stable;resuspendable; syringeable; injectable; isotonic; and nonirritating. Theforegoing characteristics result in manufacturing, storage, and usagerequirements that make injectable suspensions one of the most difficultdosage forms to develop.

Injectable suspensions are parenteral compositions in that they areintroduced into an organism or host by means other than through thegastrointestinal tract. Particularly, injectable suspensions areintroduced into a host by subcutaneous (SC) or intramuscular (IM)injection. Injectable suspensions may be formulated as a ready-to-useinjection or require a reconstitution step prior to use. Injectablesuspensions typically contain between 0.5% and 5.0% solids, with aparticle size of less than 5 μm for IM or SC administration. Parenteralsuspensions are frequently administered through needles about one-halfto two inches long, 19 to 22 gauge, with an internal diameter in therange of 700 to 400 microns, respectively.

To develop an effective and pharmaceutically acceptable injectablesuspension, a number of characteristics must be evaluated. Thesecharacteristics include syringeability, injectability, clogging,resuspendability, and viscosity. As will be readily apparent to oneskilled in the art, other characteristics and factors should beconsidered in developing an injectable suspension (see, for example,Floyd, A. G. and Jain, S., Injectable Emulsions and Suspensions, Chapter7 in Pharmaceutical Dosage Forms: Disperse Systems Vol. 2, Edited byLieberman, H. A., Rieger, M. M., and Banker, G. S., Marcel Dekker, NewYork (1996), the entirety of which is incorporated herein by referenceand referred to herein as “the Floyd et al. Chapter”).

Syringeability describes the ability of an injectable suspension to passeasily through a hypodermic needle on transfer from a vial prior toinjection. It includes characteristics such as ease of withdrawal,clogging and foaming tendencies, and accuracy of dose measurements. Asdescribed in the Floyd et al. Chapter, increase in the viscosity,density, particle size, and concentration of solids in suspensionhinders the syringeability of suspensions.

Injectability refers to the performance of the suspension duringinjection. Injectability includes factors such as pressure or forcerequired for injection, evenness of flow, aspiration qualities, andfreedom from clogging.

Clogging refers to the blockage of syringe needles while administering asuspension. It may occur because of a single large particle, or anaggregate that blocks the lumen of the needle due to a bridging effectof the particles. Clogging at or near the needle end may be caused byrestrictions to flow from the suspension. This may involve a number offactors, such as the injection vehicle, wetting of particles, particlesize and distribution, particle shape, viscosity, and flowcharacteristics of the suspension.

Resuspendability describes the ability of the suspension to uniformlydisperse with minimal shaking after it has stood for some time.Resuspendability can be a problem for suspensions that undergo “caking”upon standing due to settling of the deflocculated particles. “Caking”refers to a process by which the particles undergo growth and fusion toform a nondispersible mass of material.

Viscosity describes the resistance that a liquid system offers to flowwhen it is subjected to an applied shear stress. A more viscous systemrequires greater force or stress to make it flow at the same rate as aless viscous system. A liquid system will exhibit either Newtonian ornon-Newtonian flow based on a linear or a non-linear increase,respectively, in the rate of shear with the shearing stress. Structuredvehicles used in suspensions exhibit non-Newtonian flow and aretypically plastic, pseudoplastic, or shear-thinning with some thixotropy(exhibiting a decrease in viscosity with an increase in the rate ofshear).

In design of injection vehicles, viscosity enhancers are added in orderto retard settling of the particles in the vial and syringe. However,viscosity is typically kept low, in order to facilitate mixing,resuspension of the particles with the vehicle, and to make thesuspension easier to inject (i.e., low force on the syringe plunger).For example, Lupron Depot from TAP Pharmaceuticals (mean particle sizeof approximately 8 μm) utilizes an injection vehicle with a viscosity ofapproximately 5.4 cp. The fluid phase of a suspension of Decapeptyl fromDebioPharm (mean particle size of approximately 40 μm), when prepared asdirected, has a viscosity of approximately 19.7 cp. Conventionalparenteral suspensions are dilute, with limitations for viscositybecause of syringeability and injectability constraints. See, forexample, the Floyd, et al. Chapter noted above.

Injectable compositions containing microparticle preparations areparticularly susceptible to injectability problems. Microparticlesuspensions may contain 10-15% solids, as compared with 0.5-5% solids inother types of injectable suspensions. Microparticles, particularlycontrolled release microparticles containing an active agent or othertype of substance to be released, range in size up to about 250 μm, ascompared with a particle size of less than 5 μm recommended for IM or SCadministration. The higher concentration of solids, as well as thelarger solid particle size, make it more difficult to successfullyinject microparticle suspensions. This is particularly true since it isalso desired to inject the microparticle suspensions using as small aneedle as possible to minimize patient discomfort.

Thus, there is a need in the art for an injectable composition withimproved injectability. There is a particular need in the art for aninjectable composition that solves the injectability problems associatedwith microparticle suspensions. The present invention, the descriptionof which is fully set forth below, solves the need in the art for suchinjectable compositions.

SUMMARY OF THE INVENTION

The present invention relates to injectable compositions having improvedinjectability, and to methods for the preparation of such injectablecompositions. In one aspect of the invention, a composition suitable forinjection through a needle into a host is provided. The compositioncomprises microparticles having a polymeric binder, with a mass mediandiameter of at least about 10 μm. The composition also includes anaqueous injection vehicle (the injection vehicle not being the aqueousinjection vehicle that consists of 3% by volume sodium carboxymethylcellulose, 1% by volume polysorbate 20, 0.9% by volume sodium chloride,and a remaining percentage by volume of water). The microparticles aresuspended in the injection vehicle at a concentration of greater thanabout 30 mg/ml to form a suspension, the fluid phase of the suspensionhaving a viscosity of at least 20 cp at 20° C. In other embodiments, thefluid phase of the suspension has a viscosity at 20° C. of at leastabout 30 cp, 40 cp, 50 cp, and 60 cp. The composition may also comprisea viscosity enhancing agent, a density enhancing agent, a tonicityenhancing agent, and/or a wetting agent. The composition can beadministered to a host by injection.

In another aspect of the present invention, a method of making acomposition suitable for injection through a needle into a host isprovided. The method comprises:

-   -   (a) providing microparticles comprising a polymeric binder, said        microparticles having a mass median diameter of at least about        10 μm;    -   (b) providing an aqueous injection vehicle having a viscosity of        at least 20 cp at 20° C., wherein said injection vehicle is not        the aqueous vehicle consisting of 3% by volume sodium        carboxymethyl cellulose, 1% by volume polysorbate 20, 0.9% by        volume sodium chloride, and a remaining percentage by volume of        water; and    -   (c) suspending the microparticles in the aqueous injection        vehicle at a concentration of greater than about 30 mg/ml to        form a suspension.

In a further aspect of the present invention, another method forpreparing a composition suitable for injection through a needle into ahost is provided. In such a method, dry microparticles are mixed with anaqueous injection vehicle to form a first suspension. The firstsuspension is mixed with a viscosity enhancing agent to form a secondsuspension. The viscosity enhancing agent increases the viscosity of thefluid phase of the second suspension. The first suspension may bewithdrawn into a first syringe, prior to mixing with the viscosityenhancing agent. The first suspension may be mixed with the viscosityenhancing agent by coupling the first syringe containing the firstsuspension to a second syringe that contains the viscosity enhancingagent. The first suspension and the viscosity enhancing agent are thenrepeatedly passed between the first and second syringes.

In yet a further aspect of the present invention, a method foradministering a composition to a host is provided. The method comprises:

-   -   (a) mixing dry microparticles with an aqueous injection vehicle        to form a first suspension;    -   (b) mixing the first suspension with a viscosity enhancing agent        to form a second suspension, wherein the viscosity enhancing        agent increases the viscosity of the fluid phase of the second        suspension; and    -   (c) injecting the second suspension into the host.

In still a further aspect of the present invention, another method foradministering a composition to a host is provided. The method comprises:

-   -   (a) mixing dry microparticles with an aqueous injection vehicle        to form a suspension, wherein the aqueous injection vehicle has        a viscosity at 20° C. of less than about 60 cp;    -   (b) changing the viscosity of the fluid phase of the suspension;    -   (c) withdrawing the suspension into a syringe; and    -   (d) injecting the suspension from the syringe into the host.        In a further aspect of the invention, step (b) is carried out by        changing the temperature of to the fluid phase of the        suspension. In another aspect, step (c) is performed prior to        step (b). Step (b) may be carried out by adding a viscosity        enhancing agent to the suspension in the syringe to thereby        increase the viscosity of the fluid phase of the suspension.    -   In still a further aspect of the invention, a method for        preparing a composition suitable for injection through a needle        into a host is provided. The method comprises:    -   (a) mixing dry microparticles with an aqueous injection vehicle        that comprises a viscosity enhancing agent to form a suspension;    -   (b) removing water from the suspension; and    -   (c) reconstituting the suspension with a quantity of sterile        water for injection to form an injectable suspension, wherein        the quantity of sterile water for injection is sufficient to        achieve a viscosity of a fluid phase of the injectable        suspension that provides injectability of the composition        through a needle ranging in diameter from 18-22 gauge.

Features and Advantages

A feature of the present invention is that the injectable compositionscan be used to inject varying types of microparticles, and varying typesof active agents or other substances, into a host.

A further feature of the present invention is that it allowsmicroparticles to be wetted to achieve a homogeneous suspension, whileimproving injectability into a host and reducing in vivo injectabilityfailures.

The present invention advantageously provides medically acceptableinjectability rates for high concentration suspensions, and forsuspensions having large particle size.

The present invention also advantageously provides an efficient methodof improving in vivo injectability without introducing microbialcontamination or compromising aseptic conditions.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Overview

The present invention relates to injectable compositions having improvedinjectability, and to methods for the preparation of such injectablecompositions. The injectable compositions of the present inventionovercome injectability problems, particularly injectability failuresthat occur upon injection into muscle or subcutaneous tissue. Suchinjectability failures will be referred to herein as “in vivoinjectability failures.” In vivo injectability failures often manifestthemselves in the form of a plug at the tip of the needle, and occurimmediately or shortly after injection has been initiated. In vivoinjectability failures are typically not predicted by laboratory orother in vitro testing.

The inventors have unexpectedly discovered that injectability isimproved, and in vivo injectability failures significantly andunexpectedly reduced, by increasing the viscosity of the fluid phase ofan injectable suspension. This is in contrast to conventional teachingsthat an increase in the viscosity hinders injectability andsyringeability.

Viscous vehicles, however, are not optimal for preparing homogeneoussuspensions of microparticles because of the relative inability ofviscous vehicles to penetrate and wet out a mass of dry particles.Suspensions prepared with viscous vehicles are prone to clumpirreversibly. Consequently, such suspensions are not injectable vianeedles of medically acceptable size. A further disadvantage of viscoussuspensions is the lack of ease of transferring such suspensions fromthe vial or container used to prepare the suspension to the syringe usedfor injection.

The present invention also solves the additional problems that arisefrom use of a viscous injection vehicle. In accordance with the presentinvention, microparticles are suspended in an injection vehicle havingsuitable wetting characteristics. The viscosity of the fluid phase ofthe injectable suspension is increased prior to injecting the suspensionin order to improve injectability, and to reduce in vivo injectabilityfailures.

To ensure clarity of the description that follows, the followingdefinitions are provided. By “microparticles” or “microspheres” is meantparticles that contain an active agent or other substance dispersed ordissolved within a polymer that serves as a matrix or binder of theparticle. The polymer is preferably biodegradable and biocompatible. By“biodegradable” is meant a material that should degrade by bodilyprocesses to products readily disposable by the body and should notaccumulate in the body. The products of the biodegradation should alsobe biocompatible with the body. By “biocompatible” is meant not toxic tothe body, is pharmaceutically acceptable, is not carcinogenic, and doesnot significantly induce inflammation in body tissues. As used herein,“body” preferably refers to the human body, but it should be understoodthat body can also refer to a non-human animal body. By “weight %” or “%by weight” is meant parts by weight per hundred parts total weight ofmicroparticle. For example, 10 wt. % active agent would mean 10 partsactive agent by weight and 90 parts polymer by weight. Unless otherwiseindicated to the contrary, percentages (%) reported herein are byvolume. By “controlled release microparticle” or “sustained releasemicroparticle” is meant a microparticle from which an active agent orother type of substance is released as a function of time. By “massmedian diameter” is meant the diameter at which half of the distribution(volume percent) has a larger diameter and half has a smaller diameter.

METHOD AND EXAMPLES

The following examples are provided to explain the invention, and todescribe the materials and methods used in carrying out the invention.The examples are not intended to limit the invention in any manner.

Example 1 In vitro Sieve Test Study

To evaluate in vivo injectability failures, an in vitro sieve test studywas conducted to assess and predict in vivo injectability, and todetermine the key factors affecting injectability. The following factorswere investigated during the in vitro sieve test study: injectionvehicle formulation; microparticle morphology; needle diameter;suspension concentration; and particle size as exhibited by sieve screensize used to screen the microparticles during the manufacturing process.

Three batches of risperidone microparticles were manufactured at a 125gm scale using a process substantially the same as that disclosed inU.S. Pat. No. 5,792,477, the entirety of which is incorporated herein byreference (see, for example, Example 1 in U.S. Pat. No. 5,792,477).Three batches of risperidone microparticles were manufactured at a 1 Kgscale using the process described below in Example 7. All batches hadsimilar particle sizes (ranging from a Mass Median Diameter of 91 μm to121 μm) based on Hyac-Royco analysis of representative bulk materialsieved through a 180 μm sieve screen. A 160 mg or 320 mg quantity of themicroparticles (equivalent to a 50 or 100 mg dose of the risperidoneactive agent) was transferred, using a manual Perry powder filler with a5/16 inch ID barrel, into a 5 cc glass vial, and capped with a Teflonlined septum.

Two injection vehicles were used in the in vitro sieve test study. Thefirst injection vehicle (“Formula 1”) was an aqueous vehicle consistingof 1.5% by volume carboxymethyl cellulose (CMC), 30% by volume sorbitol,and 0.2% by volume Tween 20 (polysorbate 20). The viscosity of the firstinjection vehicle was approximately 27 cp at 20° C. The second injectionvehicle (“Formula 2”) was an aqueous vehicle consisting of 0.75% byvolume CMC, 15% by volume sorbitol, and 0.2% by volume Tween 20(polysorbate 20). The viscosity of the second injection vehicle wasapproximately 7 cp at 20° C.

The microparticle suspension was prepared as follows. The injectionvehicle was aspirated into a 5 cc syringe through a needle. The vehiclewas then injected into the glass vial containing the microparticles, andthe needle was removed. The glass vial was then rolled between the palmsuntil the microparticles were completely suspended, approximately oneminute. The needle was reinserted into the vial so that the bevel of theneedle was just through the septum with the opening facing toward thevial bottom. The vial was inverted and the suspension was withdrawn. Thesyringe was rotated 180° around its axis, and the remaining suspensionwas aspirated into the syringe.

Sieve screens with mesh opening sizes of 180, 212, 250, 300, 355, and425 μm were used. The bevel of the syringe needle was placed on the meshof the sieve screen so that the bevel was in full contact with the mesh.The needle was oriented so the opening of the needle was flush againstthe mesh of the screen. This prevented the mesh from entering the bevel,while maintaining the required restrictive area. The suspension wastried on the smallest sieve mesh first (highest screen resistance). Ifthe suspension fouled the needle on this sieve mesh, the needle wasunclogged by retracting the plunger of the syringe, depressing theplunger while the syringe was in the upward position, and passing analiquot of suspension through the needle. The injection process wastried again using the next greater mesh size, and repeated until thesuspension was successfully injected. All preparations were done intriplicate.

A three-factor Box-Behnken statistical designed experiment wasconstructed to evaluate the following independent variables:manufacturing bulk sieve size (125, 150, and 180 μm); needle ID (19 TW,20 RW, and 22 RW gauge-ID of 19 TW (thin wall) equivalent to 18 RW(regular wall)); and suspension concentration (0.074, 0.096, and 0.138w/w-corresponds to approximately 300 mg microparticle dose diluted with4, 3, and 2 cc, respectively, of injection vehicle).

The following scoring system was used:

Score Result 0 Needle Block 1 Passes through a 425 μm screen 2 Passesthrough a 355 μm screen 3 Passes through a 300 μm screen 4 Passesthrough a 250 μm screen 5 Passes through a 212 μm screen

Table 1 below shows the score obtained for screen resistance tests usingthis scoring system for the 1 Kg and the 125 gm batches for each of theinjection vehicles tested.

TABLE 1 Mean Score Mfg Bulk Sieve Size n Formula 2 ≈ 7 cp Formula 1 ≈ 27cp 1 Kg Batches <180 9 2.3 2.3 <125 9 3.4 3.7 125 Gm Batches <180 6 1.52.0 <150 6 3.0 2.8 <125 6 3.0 2.5

As shown in Table 1, the screen resistance tests showed no significantdifference between the two injection vehicles tested. Variations insuspension concentration and injection vehicle viscosity showed littleto no effect. For the 1 Kg Batches, the mean scores were identical forthe <180 manufacturing bulk sieve size, even though the viscosity of theFormula 1 injection vehicle was approximately 27 cp, and the viscosityof the Formula 2 injection vehicle was significantly less, approximately7 cp. The scores for the other 1 Kg Batch and for the 125 Gm Batchesvaried modestly (0.2 to 0.5) between the two injection vehicles, therebyindicating that the injection vehicle viscosity had little effect. Thetests conducted during the in vitro sieve test study show that in vitroinjectability is strongly controlled by microparticle morphology andsize. Needle gauge had a more modest effect. As will be discussed inmore detail below, in vivo data supported the responses of microparticlemorphology, size, and suspension concentration, but contradicted theeffect of injection vehicle viscosity. Particularly, the in vivo studiesshowed a dramatic improvement in injectability with increased injectionvehicle viscosity.

In Vivo Injectability Example 2 Pig Study

The injectability of risperidone microparticles was evaluated inYorkshire weanling pigs. The study revealed that the IM injectability ofrisperidone microparticles is dependent upon injection vehicle viscosityand microparticle size. Reducing the injection vehicle viscosity led toa higher rate of injection failures due to needle clogging.

Risperidone microparticles were manufactured at the 125 gm scale in thesame manner noted above for the in vitro sieve test study. Themicroparticles were sized to <125 μm and <150 μm using USA StandardTesting Sieves Nos. 120 and 100, respectively. The same two injectionvehicles (Formula 1 and Formula 2) described above for the in vitrosieve test study were used in the pig study. 19 gauge TW×1.5 inchhypodermic needles (Becton-Dickinson Precisionglide® catalog number305187) and 3 cc hypodermic syringes (Becton-Dickinson catalog number309585) were used.

The injection experiments were conducted in male and female Yorkshireweanling pigs approximately 6 weeks in age (10-15 kg). The animals wereanesthetized with low doses of Telazole and Xylazine and with halothaneif needed. Injection sites were shaved and cleansed with betadine swabsprior to microparticle administration.

Injections to the hind quarters were administered to the biceps femorisin the upper hind limb. Injection sites in the legs were to thesuperficial digital flexor muscles in the forelimb, and to the cranialtibial muscle in the hindlimb.

Microparticles and injection vehicles were equilibrated to ambienttemperature for at least 30 minutes. Using a 3 ml syringe equipped witha 1.5 inch 19 gauge thin wall needle, the prescribed volume of injectionvehicle was withdrawn into the syringe, and injected into the vialcontaining the microparticles. The microparticles were suspended in theinjection vehicle by orienting the vial horizontally and rolling itbetween the palms of the operator's hands. This was done withoutremoving the needle/syringe from the septum. The time required to fullysuspend the microparticles was approximately one minute.

The suspended microparticles were then withdrawn into the sameneedle/syringe and injected. Following insertion of the needle and priorto injection of the suspension, the syringe plunger was withdrawnslightly to confirm that the needle was located in the extravascularspace. The time interval between aspiration of the suspension andinjection was usually less than one minute. Injection regions wereevaluated to pinpoint the site of microparticle deposition and to assessthe distribution of microparticles in the tissue.

Table 2 below shows the effect on injectability as a function ofinjection vehicle viscosity, injection site, and microparticleconcentration. A vehicle viscosity of “high” refers to the injectionvehicle of Formula 1 described above, having a viscosity ofapproximately 27 cp at 20° C. Similarly, a vehicle viscosity of “low”refers to the injection vehicle of Formula 2 described above, having aviscosity of approximately 7 cp at 20° C. The size of the microparticlesfor the results shown in Table 2 is 180 μm.

TABLE 2 Vehicle Microparticle Viscosity Dose Volume Site Failure rateHigh 160 mg 1 mL Hind quarter  0/10 High 160 mg 1 mL Leg 1/8 Low 160 mg1 mL Hind quarter 4/7 High 320 mg 1 mL Hind quarter 0/4

As can be seen from Table 2, increased failure rates were observed withthe lower viscosity injection vehicle (4 failures with 7 injections),and when the injection site was in the leg (1 failure per 8 injections).The increased failure rate due to reduced viscosity was statisticallysignificant at the 1% level (Fisher Exact Test).

Table 3 below summarizes injectability data for microparticlesfractionated by size. Similar trends were observed when the system wasstressed by decreasing the vehicle viscosity, with failure rates beinghigher with the <180 μm fraction. The <125 μm fraction and the <150 μmfraction were indistinguishable in terms of failure rate. The lowviscosity data show statistically significant differences between <180μm fraction and <150 μm fraction, and between <180 μm fraction and <125μm fraction at 1% and 3% confidence levels, respectively (Fisher ExactTest).

TABLE 3 Avg. % Max. delivered particle Vehicle Volume Failure (failedsize (μm) Viscosity (mL) Site rate injections)¹ 180 High 2.0 Leg 0/5 n/a150 High 2.0 Leg 0/5 n/a 125 High 2.0 Leg 0/5 n/a 180 High 1.0 Leg 2/4 0 150 High 1.0 Leg 0/4 n/a 125 High 1.0 Leg 0/4 n/a 180 Low 2.0 Hindquarter  8/10 33 150 Low 2.0 Hind quarter  2/10 18 125 Low 2.0 Hindquarter  3/10 80 ¹Average fraction of dose delivered prior to needleclog (failed injections only)

The in vivo pig study demonstrates a lower injectability failure ratewith a higher viscosity injection vehicle, over a range of particlesizes. The in vitro sieve test study did not predict the viscositydependence observed in the pig study.

Example 3 Sheep Study

A two-part sheep study was conducted to investigate in vivoinjectability as a function of injection vehicle composition andviscosity, and suspension concentration. In Part I, risperidonemicroparticles were prepared at the 1 Kg scale using the processdescribed below in Example 7. A batch of placebo microparticles wasprepared using the process shown and described in U.S. Pat. No.5,922,253, the entirety of which is incorporated herein by reference.The two types of microparticles were studied at two suspensionconcentrations of 150 and 300 mg/ml. Animal injectability tests wereconducted using 3 cc syringes and 22 gauge TW×1.5 inch needles(Becton-Dickinson).

Five injection vehicles were used in Part I. The five injection vehicleswere made using one or more of the three injection vehicle formulationsshown below:

Vehicle A 0.9% Saline; 0.1% Tween 20 Vehicle B 1.5% CMC; 30% Sorbitol;0.2% Tween 20 Vehicle C 3% CMC; 0.1% Tween 20; 0.9% Saline

Animal studies were conducted using domestic sheep weighingapproximately 100-150 pounds. The animals were anesthetized withTelazole/Xylazine/Atropine intramuscularly and further supplemented withisofluorane gas (approximately 1-2%) during the injection procedure.Prior to injection, the animal's dorsal, gluteal, and upper leg regionswere shaved and cleaned with alcohol. Injection sites were visualizedprior to and during dosing using ultrasound (EI Medical).

The microparticles and injection vehicles were equilibrated to ambienttemperature prior to dose suspension. Using a 3 cc syringe and 22 gaugethin-walled needle, the vehicle was aspirated and injected into themicroparticle vial. The risperidone microparticles were suspended in 1ml of vehicle at approximate concentrations of 150 or 300 mg/ml. Placebomicroparticles were suspended in 2 or 1 ml of vehicle at approximateconcentrations of 150 or 300 mg/ml. The vial was then agitated by handfor approximately 1 minute until the microparticles were suspended. Thesuspension was then aspirated back into the syringe using the sameneedle. Care was taken to recover the maximum amount of suspension fromthe vial. Preparation of dose suspensions was conducted randomly bythree individuals.

All doses were injected by a single individual into the animal almostimmediately after preparation. The rate of injection was maintainedconstant at approximately 5-10 seconds.

The results from Part I are shown in Table 4 below. Viscosities weredetermined by Brookfield Model LVT viscometer fitted with a UL adapter.Densities were measured for Vehicles A, B, and C. Densities for thecombination vehicles made up of Vehicles A, B, and C were determined byinterpolation based upon the ratio of Vehicles A, B, and C in thecombination vehicle.

TABLE 4 Viscosity Density Conc Vehicle (cp) (mg/ml) (mg/ml)² FailuresVehicle A 1.0 1.01 150 8/10 Vehicle B 24.0 1.11 150 1/10 24.0 1.11 3000/10 Vehicle C 56.0 1.04 150 0/10 56.0 1.04 150  1/10¹ 56.0 1.04 3000/10 3 Parts Vehicle B: 11.1 1.08 300 0/5  1 Part Vehicle A 1 PartVehicle B: 2.3 1.03 300 7/10 3 Parts Vehicle A ¹Placebo Microparticles.All other results are risperidone microparticles. ²mg microparticles/mldiluent

In order to isolate the effect of injection vehicle viscosity oninjectability, additional sheep injectability tests (Part II) wereconducted. The injectability results are shown below in Table 5.Viscosities were determined by Brookfield Model LVT viscometer fittedwith a UL adapter. In Part II, the suspension concentration was fixed at300 mg/ml. The tests in Part II were carried out using risperidonemicroparticles prepared in the same manner as in Part I, using the sameinjection protocol. The injection vehicles included Vehicle C andVehicle A as described above, as well as injection vehicles prepared bydiluting Vehicle C with Vehicle A. For example, the injection vehicleformulation having a viscosity of 22.9 cp is formulated by combiningVehicle C and Vehicle A in a 1:1 ratio, thereby forming Diluent 1.

TABLE 5 Viscosity Density Conc Vehicle (cp) (mg/ml) (mg/ml) FailuresVehicle C 63.8 1.04 300 2/10 1:1 Vehicle C:Diluent 1 37.6* 1.03 300 2/101:1 Vehicle C:Vehicle A 22.9 1.03 300 1/10 (Diluent 1) 1:1 Diluent1:Vehicle A 11.3 1.02 300 5/10 (Diluent 2) 1:1 Diluent 2:Vehicle A 1.41.01 300 7/10 Vehicle A 1 1.01 300 10/10  *estimate, insufficient sample

The data for Parts I and II shown in Tables 4 and 5 clearly show thatthe injection vehicle viscosity has an effect on injectability.Viscosities of at least about 20 cp are necessary for successful andmedically acceptable injectability rates. At viscosities of less than orequal to about 11 cp, in vivo injectability failures increasesignificantly.

The effect of a density enhancing agent can be seen by comparing theinjectability failures using the vehicle in Table 4 having a viscosityof 11.1 cp with the vehicle in Table 5 having a viscosity of 11.3 cp.The viscosity of these two vehicles is nearly the same. However, theTable 4 vehicle had 0/5 failures while the Table 5 vehicle had 5/10failures. The Table 4 vehicle has a higher density (1.08 mg/ml) comparedto the Table 5 vehicle (1.02 mg/ml). The Table 4 vehicle includes adensity enhancing agent, sorbitol, while the Table 5 vehicle contains nosorbitol or other density enhancing agent.

Example 4 Ex Vivo Injectability Tests

Injectability tests were conducted with several injection vehiclesprepared at viscosities exceeding ˜50 cp. Injection vehicles havingviscosities in excess of 50 cp were mixed, using a syringe-syringemixing method described in more detail in Example 5 below, in which theviscosity enhancing agent was introduced after suspending themicroparticles in the 50 cp vehicle.

Subcutaneous injections of blank (placebo) PLGA(poly(d,l-lactic-co-glycolic acid)) microparticles, having anapproximate mass median diameter of 50 μm, were made into previouslyharvested pig skin using four injection vehicles having viscosities at˜25° C. of approximately 53.1 to >1000 cp at the time of formulation.The vehicles were subsequently autoclaved before use, and the finalviscosity (viscosity of the fluid phase of the injectable suspension)varied between approximately 5-60% from the nominal starting viscosityvalue. The most viscous injection vehicle was approximately 13 times theviscosity of the 50 cp formulation. In this ex vivo model, increasingthe viscosity of the fluid phase of the injectable suspension decreasedinjection failure rate, even when microparticle concentration was raisedfrom 175 to 250 mg/ml, at a needle size of 22 G. Maximal improvement ininjectability, within this range of concentration and needle size, wasachieved with injection vehicles having a viscosity of approximately 250cp.

In another study, four injection vehicles having measured viscosities of53 to 251 cp were evaluated for subcutaneous injectability inanesthetized pigs. Microparticle concentrations were 150 and 190 mg/ml.Injection failure was directly related to microparticle concentration,and inversely related to viscosity level. At 53 cp, approximately 50% ofinjections failed, while at higher viscosities, failures diminished. Atthe highest viscosity (251 cp), zero failures were recorded at bothmicroparticle concentrations.

Example 5 Methods for Preparing Injectable Compositions

Methods for preparing injectable compositions in accordance with thepresent invention will now be described. In accordance with the presentinvention, microparticles are first mixed with an injection vehiclehaving suitable viscosity and wetting characteristics to achieve ahomogeneous mono-particulate suspension. The viscosity of the fluidphase of the suspension is then changed, preferably increased, toachieve a viscosity that inhibits suspension separation and cloggingunder conditions of normal clinical use. In accordance with one methodof the present invention, dry microparticles are mixed with an aqueousinjection vehicle to form a first suspension. The first suspension ismixed with a viscosity enhancing agent to form a second suspension. Theviscosity enhancing agent increases the viscosity of the fluid phase ofthe second suspension. The second suspension is then injected into ahost.

One embodiment for carrying out such a method will now be described.Vialed dry microparticles are mixed with an aqueous injection vehiclehaving a viscosity less than about 60 cp at 20° C., preferably about20-50 centipoise. The concentration of microparticles in the mixture isgreater than about 30 mg/ml, preferably about 100-400 mgmicroparticles/ml. The mixture is agitated until a homogeneoussuspension is formed. The homogeneous suspension is withdrawn into afirst hypodermic syringe. The first syringe is connected to a secondsyringe containing a viscosity enhancing agent. A viscosity enhancingagent suitable for use with the present invention is sodiumcarboxymethyl cellulose (CMC), preferably having a viscosity of fromabout 1000 to about 2000 cp at 20° C. It should be understood that thepresent invention is not limited to the use of CMC as the viscosityenhancing agent, and other suitable viscosity enhancing agents may beused. The added volume of the viscosity enhancing agent is approximately10-25% of the volume of the microparticle suspension.

The microparticle suspension and the viscosity enhancing agent are mixedto form the injectable composition by repeatedly passing themicroparticle suspension and the viscosity enhancing agent between thefirst and second syringes. Such a syringe-syringe mixing method was usedin the injectability tests described in Example 4 above. After mixingwith the viscosity enhancing agent, the viscosity of the fluid phase ofthe microparticle suspension is from about 200 cp to about 600 cp at 20°C. A hypodermic needle is attached to the syringe containing theinjectable composition, and the injectable composition is injected intoa host in a manner well known to one of skill in the art.

An alternate embodiment for carrying out the method of the presentinvention will now be described. Dry microparticles are mixed with anaqueous injection vehicle having a viscosity of less than about 60 cp at20° C. to form a suspension. The viscosity of the fluid phase of thesuspension is changed in a manner that will be described in more detailbelow. The suspension that constitutes the injectable composition iswithdrawn into a syringe, and the injectable composition is injectedfrom the syringe into the host. Preferably, the viscosity of the fluidphase of the suspension is changed after the suspension has beenwithdrawn into the syringe.

In one aspect of this alternate embodiment, the viscosity is changed bychanging the temperature of the fluid phase of the injectablesuspension. The methods and techniques for changing the viscosity of aliquid by changing the temperature of the liquid are readily apparent toone skilled in the art. The temperature of the fluid phase of thesuspension is changed until the desired viscosity of the fluid phase hasbeen reached. The suspension now has the desired fluid phase viscosityfor injection into a host, and constitutes the injectable composition.At this point, the suspension is withdrawn into the syringe and injectedinto the host. Alternatively, the suspension can be withdrawn into thesyringe prior to changing the temperature of the fluid phase of thesuspension to achieve the desired fluid phase viscosity. For example, aninjection vehicle that comprises a polymer solution can be used as theviscosity of polymer solutions is temperature-dependent. A polymersolution can be used to suspend the microparticles under low-viscosityconditions suitable for wetting and suspension formation. Once themicroparticles are suspended, the suspension is drawn up into a syringe.The temperature is then changed to induce higher viscosity in theinjection vehicle constituting the fluid phase of the suspension, andthe suspension having increased viscosity is injected into a host.

In another aspect of this alternate embodiment, the viscosity is changedby adding a viscosity enhancing agent to the suspension. The suspensionis withdrawn into the syringe, and then the viscosity enhancing agent isadded to the suspension in the syringe, thereby increasing the viscosityof the aqueous injection vehicle constituting the fluid phase of thesuspension. The suspension now has the desired fluid phase viscosity forinjection into a host, and constitutes the injectable composition. Thesuspension is then injected into the host. Preferably, the viscosityenhancing agent is added to the suspension immediately prior toinjection into the host. Suitable viscosity enhancing agents includesodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), such asPLASDONE, available from GAF Chemicals Corp., Wayne, N.J., andhydroxypropylmethylcellulose (HPMC), such as Methocel, available fromDow Chemical Co., Midland, Mich. However, other viscosity enhancingagents may be used, as would be readily apparent to one of skill in theart.

In another embodiment of the invention, the injectable compositions ofthe present invention are prepared by providing microparticles thatcomprise a polymeric binder and that have a mass median diameter of atleast about 10 μm. The mass median diameter of the microparticles ispreferably less than about 250 μm, and more preferably, in the range offrom about 20 μm to about 150 μm. Such microparticles can be made in themanner disclosed and described herein, or in any other manner known toone skilled in the art. An aqueous injection vehicle is provided. Suchan aqueous injection vehicle can be made in the manner disclosed anddescribed herein, or in any other manner known to one skilled in theart. The microparticles are suspended in the aqueous injection vehicleat a concentration of greater than about 30 mg/ml to form a suspension,the fluid phase of the suspension having a viscosity of at least 20 cpat 20° C.

In yet a further embodiment of the present invention, dry microparticlesare mixed with an aqueous injection vehicle containing a viscosityenhancing agent to form a suspension. Suitable viscosity enhancingagents include sodium carboxymethyl cellulose, polyvinylpyrrolidone(PVP), such as PLASDONE, available from GAF Chemicals Corp., Wayne,N.J., and hydroxypropylmethylcellulose (HPMC), such as Methocel,available from Dow Chemical Co., Midland, Mich. However, other viscosityenhancing agents may be used, as would be readily apparent to one ofskill in the art. The suspension is then dispensed into vials. The vialsare lyophilized (or vacuum dried) to remove the water. Prior toinjection, the vial contents are reconstituted with sterile water forinjection in a quantity sufficient to achieve the desired viscosity forthe fluid phase of the reconstituted injectable suspension. Preferably,the vial contents are reconstituted with a quantity of sterile water forinjection sufficient to achieve a viscosity of a fluid phase of theinjectable suspension that provides injectability of the compositionthrough a needle ranging in diameter from 18-22 gauge.

Example 6 Injectable Compositions

The injectable compositions of the present invention will now bedescribed. The injectable compositions of the present invention aresuitable for injection through a needle into a host. In one embodiment,the injectable compositions comprise microparticles suspended in anaqueous injection vehicle. The microparticles preferably have a massmedian diameter of at least about 10 μm to about 250 μm, preferably inthe range of from about 20 μm to about 150 μm. However, it should beunderstood that the invention is not limited to microparticles in thissize range, and that smaller or larger microparticles may also be used.

The microparticles preferably comprise a polymeric binder. Suitablepolymeric binder materials include poly(glycolic acid), poly-d,l-lacticacid, poly-l-lactic acid, copolymers of the foregoing, poly(aliphaticcarboxylic acids), copolyoxalates, polycaprolactone, polydioxanone,poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone),polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides,polyphosphazines, albumin, casein, and waxes.Poly(d,l-lactic-co-glycolic acid) is commercially available fromAlkermes, Inc. (Blue Ash, Ohio). A suitable product commerciallyavailable from Alkermes, Inc. is a 50:50 poly(d,l-lactic-co-glycolicacid) known as MEDISORB® 5050 DL. This product has a mole percentcomposition of 50% lactide and 50% glycolide. Other suitablecommercially available products are MEDISORB® 6535 DL, 7525 DL, 8515 DLand poly(d,l-lactic acid) (100 DL). Poly(lactide-co-glycolides) are alsocommercially available from Boehringer Ingelheim (Germany) under itsResomer® mark, e.g., PLGA 50:50 (Resomer® RG 502), PLGA 75:25 (Resomer®RG 752) and d,l-PLA (Resomer® RG 206), and from Birmingham Polymers(Birmingham, Ala.). These copolymers are available in a wide range ofmolecular weights and ratios of lactic acid to glycolic acid.

One type of microparticle suitable for use with the present invention isa sustained-release microparticle that is biodegradable. However, itshould be understood by one skilled in the art that the presentinvention is not limited to biodegradable or other types ofsustained-release microparticles. As would be apparent to one skilled inthe art, the molecular weight of the polymeric binder material forbiodegradable microparticles is of some importance. The molecular weightshould be high enough to permit the formation of satisfactory polymercoatings, i.e., the polymer should be a good film former. Usually, asatisfactory molecular weight is in the range of 5,000 to 500,000daltons, preferably about 150,000 daltons. However, since the propertiesof the film are also partially dependent on the particular polymericbinder material being used, it is very difficult to specify anappropriate molecular weight range for all polymers. The molecularweight of the polymer is also important from the point of view of itsinfluence upon the biodegradation rate of the polymer. For a diffusionalmechanism of drug release, the polymer should remain intact until all ofthe drug is released from the microparticles and then degrade. The drugcan also be released from the microparticles as the polymeric binderbioerodes. By an appropriate selection of polymeric materials amicroparticle formulation can be made in which the resultingmicroparticles exhibit both diffusional release and biodegradationrelease properties. This is useful in according multiphasic releasepatterns.

The microparticles may include an active agent or other type ofsubstance that is released from the microparticles into the host. Suchactive agents can include 1,2-benzazoles, more particularly,3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles.The most preferred active agents of this kind are3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(“risperidone”) and3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(“9-hydroxyrisperidone”) and the pharmaceutically acceptable saltsthereof. Risperidone (which term, as used herein, is intended to includeits pharmaceutically acceptable salts) is most preferred. Risperidonecan be prepared in accordance with the teachings of U.S. Pat. No.4,804,663, the entirety of which is incorporated herein by reference.9-hydroxyrisperidone can be prepared in accordance with the teachings ofU.S. Pat. No. 5,158,952, the entirety of which is incorporated herein byreference.

Other biologically active agents include non-steroidal antifertilityagents; parasympathomimetic agents; psychotherapeutic agents;tranquilizers; decongestants; sedative hypnotics; steroids;sulfonamides; sympathomimetic agents; vaccines; vitamins; antimalarials;anti-migraine agents; anti-Parkinson agents such as L-dopa;anti-spasmodics; anticholinergic agents (e.g. oxybutynin); antitussives;bronchodilators; cardiovascular agents such as coronary vasodilators andnitroglycerin; alkaloids; analgesics; narcotics such as codeine,dihydrocodienone, meperidine, morphine and the like; non-narcotics suchas salicylates, aspirin, acetaminophen, d-propoxyphene and the like;opioid receptor antagonists, such as naltrexone and naloxone;antibiotics such as gentamycin, tetracycline and penicillins;anti-cancer agents; anti-convulsants; anti-emetics; antihistamines;anti-inflammatory agents such as hormonal agents, hydrocortisone,prednisolone, prednisone, non-hormonal agents, allopurinol,indomethacin, phenylbutazone and the like; prostaglandins and cytotoxicdrugs.

Still other suitable active agents include estrogens, antibacterials;antifungals; antivirals; anticoagulants; anticonvulsants;antidepressants; antihistamines; and immunological agents.

Other examples of suitable biologically active agents include peptidesand proteins, analogs, muteins, and active fragments thereof, such asimmunoglobulins, antibodies, cytokines (e.g. lymphokines, monokines,chemokines), blood clotting factors, hemopoietic factors, interleukins(IL-2, IL-3, IL-4, IL-6), interferons (β-IFN, α-IFN and γ-IFN),erythropoietin, nucleases, tumor necrosis factor, colony stimulatingfactors (e.g., GCSF, GM-CSF, MCSF), insulin, enzymes (e.g., superoxidedismutase, tissue plasminogen activator), tumor suppressors, bloodproteins, hormones and hormone analogs (e.g., growth hormone,adrenocorticotropic hormone and luteinizing hormone releasing hormone(LHRH)), vaccines (e.g., tumoral, bacterial and viral antigens);somatostatin; antigens; blood coagulation factors; growth factors (e.g.,nerve growth factor, insulin-like growth factor); protein inhibitors,protein antagonists, and protein agonists; nucleic acids, such asantisense molecules; oligonucleotides; and ribozymes. Small molecularweight agents suitable for use in the invention include, antitumoragents such as bleomycin hydrochloride, carboplatin, methotrexate andadriamycin; antipyretic and analgesic agents; antitussives andexpectorants such as ephedrine hydrochloride, methylephedrinehydrochloride, noscapine hydrochloride and codeine phosphate; sedativessuch as chlorpromazine hydrochloride, prochlorperazine hydrochloride andatropine sulfate; muscle relaxants such as tubocurarine chloride;antiepileptics such as sodium phenyloin and ethosuximide; antiulceragents such as metoclopramide; antidepressants such as clomipramine;antiallergic agents such as diphenhydramine; cardiotonics such astheophillol; antiarrhythmic agents such as propranolol hydrochloride;vasodilators such as diltiazem hydrochloride and bamethan sulfate;hypotensive diuretics such as pentolinium and ecarazine hydrochloride;antidiuretic agents such as metformin; anticoagulants such as sodiumcitrate and heparin; hemostatic agents such as thrombin, menadionesodium bisulfite and acetomenaphthone; antituberculous agents such asisoniazide and ethanbutol; hormones such as prednisolone sodiumphosphate and methimazole.

The microparticles can be mixed by size or by type. However, it shouldbe understood that the present invention is not limited to the use ofbiodegradable or other types of microparticles that contain an activeagent. In one embodiment, the microparticles are mixed in a manner thatprovides for the delivery of active agent to the patient in amultiphasic manner and/or in a manner that provides different activeagents to the patient at different times, or a mixture of active agentsat the same time. For example, secondary antibiotics, vaccines, or anydesired active agent, either in microparticle form or in conventional,unencapsulated form can be blended with a primary active agent andprovided to the patient.

The microparticles are preferably suspended in the injection vehicle ata concentration of greater than about 30 mg/ml. In one embodiment, themicroparticles are suspended at a concentration of from about 150 mg/mlto about 300 mg/ml. In another embodiment, the microparticles aresuspended at a concentration of from about 100 mg/ml to about 400 mg/ml.However, it should be understood that the invention is not limited to aparticular concentration.

The aqueous injection vehicle preferably has a viscosity of at least 20cp at 20° C. In one embodiment, the injection vehicle has a viscositygreater than 50 cp and less than 60 cp at 20° C. The viscosity of theinjection vehicle preferably provides injectability of the compositionthrough a needle ranging in diameter from 18-22 gauge. As known to oneskilled in the art, an 18 gauge regular wall (RW) needle has a nominalinner diameter (ID) of 0.033 in., and a 22 gauge regular wall needle hasa nominal inner diameter of 0.016 in.

The injection vehicle may comprise a viscosity enhancing agent. Apreferred viscosity enhancing agent is sodium carboxymethyl cellulose,although other suitable viscosity enhancing agents may also be used. Theinjection vehicle may also comprise a density enhancing agent thatincreases the density of the injection vehicle. A preferred densityenhancing agent is sorbitol, although other suitable density enhancingagents may also be used. The injection vehicle may also comprise atonicity adjusting agent to adjust the tonicity to preclude toxicityproblems and improve biocompatibility. A preferred tonicity adjustingagent is sodium chloride, although other suitable tonicity adjustingagents may also be used.

The injection vehicle may also comprise a wetting agent to ensurecomplete wetting of the microparticles by the injection vehicle.Preferred wetting agents include polysorbate 20 (Tween 20), polysorbate40 (Tween 40), and polysorbate 80 (Tween 80).

One preferred injection vehicle is an aqueous injection vehicle thatcomprises 1.5% sodium carboxymethyl cellulose, 30% sorbitol, and 0.2%polysorbate 20. Another preferred injection vehicle is an aqueousinjection vehicle that comprises 3% sodium carboxymethyl cellulose, 0.9%saline, and 0.1% polysorbate 20.

Example 7 1 Kg Process

A process for preparing microparticles containing risperidone as theactive agent will now be described. The following 1 Kg process (400grams of active agent and 600 grams of polymer) is for a theoreticaldrug loading of the microparticles of 40%. The actual drug loading thatis achieved by the process described below ranges from about 35% toabout 39%.

A drug solution is prepared by dissolving 400 grams of risperidone(Janssen Pharmaceutica, Beerse, Belgium) in 1267 grams of benzyl alcoholto form a 24 wt. % drug solution. A polymer solution is formed bydissolving 600 grams of MEDISORB® 7525 DL polymer (Alkermes, Inc., BlueAsh, Ohio) in 3000 grams of ethyl acetate to form a 16.7 wt. % polymersolution. The drug solution and the polymer solution are combined toform a first, discontinuous phase.

The second, continuous phase is prepared by preparing a 30 litersolution of 1% PVA, the PVA acting as an emulsifier. To this is added2086 grams of ethyl acetate to form a 6.5 wt. % solution of ethylacetate.

The two phases are combined using a static mixer, such as a ½″ Kenicsstatic mixer available from Chemineer, Inc., North Andover, Mass. Atotal flow rate of 3 L/min generally provides microparticle sizedistributions with a mass median diameter (MMD) in the range of about80-90μ. The ratio of continuous phase to discontinuous phase is 5:1(v/v). The length of the static mixer can vary from about 9 inches toabout 88 inches. Lengths greater than about 48 inches results in thegreatest percent yield in a microparticle size range of 25-150μ.

The quench liquid is 2.5% solution of ethyl acetate andwater-for-injection (WFI) at 5-10° C. The volume of the quench liquid is0.25 L per gram of batch size. The quench step is carried out for a timeperiod greater than about 4 hours, with stirring of the microparticlesin the quench tank.

After completion of the quench step, the microparticles are transferredto a collecting, de-watering, and drying device. The microparticles arerinsed using a chilled (approximately 5° C.) 17 liter 25% ethanolsolution. The microparticles are dried, and then re-slurried in are-slurry tank using a 25% ethanol solution (extraction medium)maintained at a temperature lower than the T_(g) (glass transitiontemperature) of the microparticles. The microparticles are thentransferred back to the quench tank for washing for a time period of atleast 6 hours with another extraction medium (25% ethanol solution) thatis maintained at a temperature higher than the T_(g) of themicroparticles. The T_(g) of the microparticles is about 18° C. (aboutroom temperature), and the temperature of the extraction medium in thequench tank is greater than about 18° C., preferably 25°±1° C.

The microparticles are transferred back to the collecting, de-watering,and drying device for de-watering and final drying. Drying continues fora time period greater than about 16 hours.

CONCLUSION

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofexample only, and not limitation. The present invention is not limitedto controlled release microparticle injectable suspensions, nor is itlimited to a particular active agent, polymer or solvent, nor is thepresent invention limited to a particular scale or batch size. Thus, thebreadth and scope of the present invention should not be limited by anyof the above-described exemplary embodiments, but should be defined onlyin accordance with the following claims and their equivalents.

1. A composition suitable for injection through a needle into a host,comprising: microparticles comprising a polymeric binder and an activeagent encapsulated within the polymeric binder, the microparticleshaving a mass median diameter of at least about 10 μm; and an injectionvehicle, wherein the microparticles are suspended in the injectionvehicle at a concentration of greater than about 30 mg/ml to form asuspension, wherein a fluid phase of the suspension has a viscositygreater than about 20 cp and less than about 600 cp at 20° C., whereinthe viscosity of the fluid phase of the suspension providesinjectability of the composition through a needle into a host, whereinthe polymeric binder is selected from the group consisting ofpoly(glycolic acid), poly-d,l-lactic acid; poly-l-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, polyphosphazines,albumin, and casein, wherein the injection vehicle comprises a viscosityenhancing agent comprising sodium carboxymethyl cellulose; a wettingagent selected from the group consisting of polysorbate 20, polysorbate40, and polysorbate 80; and a tonicity adjusting agent comprising sodiumchloride, and wherein the viscosity of the fluid phase of the suspensionprovides injectability of the composition into a host through a needleof medically acceptable size.
 2. The composition of claim 1, wherein theactive agent is selected from the group consisting of risperidone,9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof. 3.The composition of claim 1, wherein the polymeric binder ispoly(d,l-lactide-co-glycolide) having a molar ratio of lactide toglycolide in the range of from about 85:15 to about 50:50.
 4. Thecomposition of claim 1, wherein the microparticles are suspended in theinjection vehicle at a concentration of from about 100 mg/ml to about400 mg/ml.
 5. The composition of claim 1, wherein the viscosity of thefluid phase of the suspension provides injectability of the compositioninto the host through a needle ranging in diameter from 18-22 gauge. 6.The composition of claim 1, wherein the injection vehicle is aqueous. 7.A method of making a composition suitable for injection through a needleinto a host, comprising: (a) providing microparticles comprising apolymeric binder and an active agent encapsulated within the polymericbinder, the microparticles having a mass median diameter of at leastabout 10 μm; (b) providing an injection vehicle having a viscosity of atleast 20 cp at 20° C.; and (c) suspending the microparticles in theinjection vehicle at a concentration of greater than about 30 mg/ml toform a suspension, wherein the viscosity of a fluid phase of thesuspension is in the range of from about 20 cp to about 600 cp at 20°C., wherein the viscosity of the fluid phase of the suspension providesinjectability of the composition into a host through a needle ofmedically acceptable size, wherein the polymeric binder is selected fromthe group consisting of poly(glycolic acid), poly-d,l-lactic acid;poly-l-lactic acid, copolymers of the foregoing, poly(aliphaticcarboxylic acids), copolyoxalates, polycaprolactone, polydioxanone,poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone),polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides,polyphosphazines, albumin, and casein, and wherein the viscosityenhancing agent comprises sodium carboxymethyl cellulose.
 8. The methodof claim 7, wherein the active agent is selected from the groupconsisting of risperidone, 9-hydroxyrisperidone, and pharmaceuticallyacceptable salts thereof.
 9. The method of claim 7, wherein thepolymeric binder is poly(d,l-lactide-co-glycolide) having a molar ratioof lactide to glycolide in the range of from about 85:15 to about 50:50.10. The method of claim 7, wherein the viscosity of the fluid phase ofthe suspension provides injectability of the composition into the hostthrough a needle ranging in diameter from 18-22 gauge.
 11. The method ofclaim 7, wherein the microparticles are suspended in the injectionvehicle at a concentration of from about 100 mg/ml to about 400 mg/ml.12. The method of claim 7, wherein the injection vehicle is aqueous.